1.1 Table of Contents

The overall table of contents should include all modules from 1 to 5.

1.2  Correspondence

1.1.2 Copy of the letter from the manufacturer indicating the intention to submit an application for prequalification of the vaccine, and a copy of the letter from WHO acknowledging the acceptability for submission.

1.2.2 Mutually-agreed minutes of any pre-submission meetings between WHO and the applicant.

1.3  Site master file

Must be consistent with the relevant WHO Guidance document:WHO Technical Report Series, No. 961, Annex 14, 2011

1.4  Compliance information

1.4.1. Certificate of Establishment Licensing, if required and provided by the national regulatory authority (NRA) of the country of manufacture.

1.4.2. Copy of GMP certificate, or other evidence of GMP compliance issued by the NRA of the country of manufacture. Report (English translation if required) of the last GMP inspection (which included in its scope the production of the product submitted for prequalification) by the NRA of the country of manufacture

1.4.3. Copy of marketing authorizations for all formulations and presentations in the country of manufacture and/or the country of reference of the vaccine submitted for prequalification, or the European Medicines Agency scientific opinion for Article 58 products.

1.4.4. Policy for assignment of date of manufacture of each component as well as the final product and diluents.

1.4.5 If the vaccine contains or consists of genetically modified organisms (GMOs), supply a copy of the Environmental Risk Assessment.

Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC Commission Declarationdefines a GMO as: an organism in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination.

Council Directive 90/220/EEC of 23 April 1990 on the deliberate release into the environment of genetically modified organismsdefines an environmental risk assessment as: the evaluation of the risk to human health and the environment (which includes plants and animals) connected with the release of GMOs or products containing GMOs.

1.5  Vaccine composition, presentations and scheduling information

1.5.1. Description of presentations available to UN agencies, including diluent (if applicable), combination products, forms, dose sizes and type of containers and indicate vaccine vial monitor (VVM) type and location.

1.5.2 Vaccine temperature stability profile. Additional to stability information in Module 3.2.P.8, please provide any additional stability data required to support the assignment of VVM type or to support any on-label claim for elevated temperature storage according to guidelines for extended controlled temperature conditions.

1.5.3 Description of immunization /administration devices to be delivered with the vaccine.

1.5.4 Recommended schedule and route of administration.

1.5.5 Artworks or mockups of labels of primary containers and secondary packaging for the product (including diluents, if applicable). Artworks and mockups may be submitted in English for review of the content.

1.5.6 Samples of package inserts (in English) to be used for supply through UN agencies. After finalization of the review of the English version, packaging inserts must be translated to other languages required by UN procurement agencies (currently French, Portuguese, Russian and Spanish), and the translations provided.

1.5.7 Template of lot summary protocol to be provided to UN agencies, in compliance with WHO-recommended format.

1.5.8 Self-assessment against programmatic suitability for prequalification criteria. See Assessment the programmatic stability of vaccines candidates for WHO prequalification. 

1.6  Supplemental preclinical and clinical information (Pre- and post-marketing)

Note: This section applies only in the case that data is not already included in the national regulatory authority submission, or as a part of Modules 2 to 5 submitted for prequalification.

1.6.1 List of preclinical studies sponsored by applicant – not included in Module 2.6 and Module 4 of the application- including any conclusion(s) and any preclinical studies performed after initial licensure of product (and the rationale for these studies).

1.6.2 List of all clinical trials sponsored by the applicant relevant for the application that are not included in Module 5.2 of the application. This list must contain the following information about each clinical trial described in this section:

• location of study sites
• number and age of subject
• date of study
• evidence of registration in clinical registry (part of WHO International Clinical Trials Registry Platform)
• indication of whether the study complied with good clinical practice (GCP)
• rational of the study (to be included in the summary table)
• statement of final conclusions on safety and immunogenicity (and/or efficacy).

1.6.3 Cross reference to the final protocol approved by the Ethics and Research Committee (ERC) and the national regulatory authority (NRA).

1.6.4 List of any clinical trials that are known to be currently ongoing with the vaccine candidate but not relevant to the current WHO prequalification application. This should include the summary of details of the study plan and expected date of result (for example, clinical trials being conducted for a different use indication and/or with a different age group, etc.).

1.6.5 List of other studies with applicant product – not included in Module 5 - for which the applicant is not the sponsor.

The applicant should make every effort to provide a list of all trials and, where applicable, observational studies relevant to the application that were not sponsored by the applicant but in which the product was evaluated. This list should be compiled from publications identified using an extensive literature search (details of which should be provided) and, in the case of co-licensure agreements, from any other company that holds a licence for or a right to market the same product.

1.6.6 Complementary clinical summary supporting the use of the product worldwide by UN agencies

Provide a detailed summary and interpretation of the safety and efficacy data obtained from the pre-licensure clinical studies and all studies performed in the post-licensure period that support the current prescribing information. The summary should pay particular attention to any data that are relevant to the use of the product worldwide in WHO recommended schedules (for example, co-administration of other vaccines). In the absence of such data, the summary should provide a preclinical and/or clinical justification for the extrapolation of the existing data to the likely circumstances of use after prequalification. This summary should complement, and not replace, the summary written by an independent clinical expert described in Module section 1.6.8 above.

Consistency of manufacturing for the vaccine lots used in clinical trials should be demonstrated and well documented. It is ideal that at least three lots with the same formulation intended for marketing are used in the late stages of the clinical development programme. However, a formal lot-to-lot consistency clinical study is considered only on a case-by-case basis, in particular when assessing vaccine formulations with inherent variability.

It is important to note that there are a number of significant considerations in the event that the manufacturer decides to perform a lot-to-lot consistency clinical study to fulfil the requirements for vaccine licensure of an  NRA. Vaccines used in clinical-consistency trials must have been manufactured at commercial scale. The study should be designed (and analysed) as an equivalence trial and have a pre-defined criteria and choice of parameters to conclude comparability.

Changes to the batch size used to produce the clinical lots will require additional information to support the change (for example, scale-up). Depending on the manufacturing consistency data, additional clinical studies to support comparability to the clinical lots may be required. These issues should be decided in consultation with the WHO Prequalification Team.

1.6.7 Assessment report from the NRA(s)

Whenever possible, the applicant should provide the reference NRA assessment reports from the country of origin and/or country where the vaccine is initially licensed. Assessment reports for both initial licensure and any subsequent variations to the licence for changes relevant to clinical data are requested.

1.6.8. Clinical independent expert report

Provide an independent clinical expert report on the clinical studies (evidence of expertise and independence should be provided). If the application for prequalification is based on the extrapolation of the existing clinical data to the likely circumstances of use after prequalification, and if the data are old or there is a doubt regarding the ethical or regulatory oversight of the trial, the report should discuss the degree of compliance with WHO GCP recommendations and current guidance regarding preclinical and clinical trials with vaccines.

1.6.9 Post-marketing safety documentation

Safety data should be submitted both in the case of the initial application for prequalification evaluation and for reassessment purposes.

1.6.9.1 Outline of the post-marketing pharmacovigilance plan for the product or Risk Management Plan.

1.6.9.2. Initial evaluation of vaccines that have been in the market for more than five years or reassessment of already prequalified vaccines. (The latest PSUR may be provided.)

Outline of the applicant’s procedures for the collection, onward notification and assessment of adverse events following immunization (AEFIs).

Listing of all reported AEFIs for the vaccine in question in the last five years or since the last WHO reassessment. As far as is possible from the reports received, applicants should list the type of reaction, lot number, date and place of immunization, patients’ initials and age and, for immunization series, the dose number. A judgment of seriousness and whether or not the event was expected (in the light of the prescribing to the vaccine made by a clinician and, where relevant, by the applicant company or its independent clinical expert, should be included.

1.6.9.3 List of ongoing clinical studies for vaccines licensed within the last five years. Add a cross reference to Module 5 and any studies that may not be part of the CTD. This includes Phase IV studies or any active monitoring of safety profile of the vaccine.

1.7  Regulatory actions

1.7.1 Information on refusals, withdrawals, suspensions, including those initiated by the manufacturer 1.7.2. List of lots rejected by a national regulatory authority (NRA), if applicable.

1.7.3. Restrictions on distributions and recalls of lots, including those initiated by the manufacturer

1.7.4. Any clinical trial suspensions.

1.7.5. Dosage or schedule changes since the initial marketing authorization in the country of manufacture and/or the country of reference.

1.7.6. Changes in target populations since the initial marketing authorization in the country of manufacture and/or the country of reference.

1.8  Distribution information

1.8.1. Quantity of finished product distributed in the domestic market of the country of manufacture and/or the country of reference and exported in the last three years, by presentation. Clearly indicate if numbers refer to vials or doses.

1.8.2. List of countries where the product has received a marketing authorization, indicating whether the product has been supplied in those countries.

1.8.3. Description of the release process by the NRA/national control laboratory and recording system for distribution.

1.8.4 Summary of the packaging procedures for international shipments for UN agencies and the validation (according to relevant, current WHO guidelines) of this packaging.

The content of Modules 2, 3, 4 and 5 should be prepared in accordance with the M4Q, M4S and M4E guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. A summary of the contents to be included in each module is given below.

Module 2: Common Technical Document (CTD) Summaries (see ICH guidelines M4Q, M4S, M4E)

2.1  Common technical document table of contents (Modules 2‒5)

2.2  CTD introduction

2.3  Quality overall summary

2.4  Nonclinical overview

2.5  Clinical overview

2.6  Nonclinical written and tabulated summaries: pharmacology, pharmacokinetics, toxicology

2.7  Clinical summary biopharmaceutic studies and associated analytical methods Clinical Pharmacology Studies Clinical Efficacy Clinical Safety Literature References Synopses of Individual Studies

Module 3: Quality (see ICH guideline M4Q)

3.1  Table of contents of Module 3

3.2  Body of data

3.3  Literature references

Module 4: Nonclinical study reports (as per ICH M4S)

4.1  Table of Contents of Module

4.2  Study Reports

4.3  Literature References

Module 5: Clinical study reports (see ICH guideline M4E)

5.1 Table of Contents of Module 5

5.2 Tabular listing of all clinical studies

5.3 Clinical study reports

5.4 Literature references